Controlled release formulation of divalproex sodium

ABSTRACT

A new oral polymeric controlled release formulation suitable for the once-a-day administration of valproate compounds, such as divalproex sodium, has been discovered. This formulation exhibits significant advantages over the sustained release valproate formulations of the prior art. This formulation minimizes the variation between peak and trough plasma levels of valproate over a 24 hour dosing period. This formulation follows a zero-order release pattern thus producing essentially flat plasma levels of valproate, once steady-state levels have been achieved. This results in a significantly lower incidence of side effects for patients consuming such a formulation.

CROSS REFERENCE

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/216,650, filed Dec. 18, 1998, the contents ofwhich are hereby incorporated by reference.

TECHNICAL FIELD

[0002] The present invention relates to pharmaceutical formulations.More particularly, the present invention concerns a formulationcomprising valproic acid, a pharmaceutically acceptable salt, ester, oramide thereof, or divalproex sodium, in a controlled releaseformulation. These controlled release dosage forms have an improvedpharmacokinetic profile. These dosage forms minimize the variancebetween peak and trough plasma levels of valproate, resulting in areduction in the incidence of side effects.

BACKGROUND

[0003] 2-Propylpentanoic acid, more commonly known as valproic acid(“VPA”) is effective as an antiepilpetic agent. After ingestion, thefree acid dissociates to the valproate ion within the gastrointestinaltract. The valproate ion is absorbed and produces the therapeutic effectdescribed above. Physicians Desk Reference (“PDR”), 52nd Edition, page426 (2000).

[0004] Divalproex sodium is effective in the treatment of epilepsy,migraine, and bipolar disorders. It also dissociates to the valproateion within the gastrointestinal tract. This substance is described inmore detail in U.S. Pat. No. 4,988,731, and U.S. Pat. No. 5,212,326, thecontents of both, which are hereby incorporated by reference.

[0005] The acid moiety of valproic acid has been functionalized in orderto produce prodrugs capable of generating a valproate ion in-vivo. Forexample, the amide of valproic acid, valpromide (“VPO”), has beenproduced, as well certain salts and esters of the acid.

[0006] Despite the efficacy of these drugs in the treatment ofconditions such as epilepsy, they all suffer from a common disadvantage.These valproate compounds have a relatively short half life. Forexample, the half life of valproic acid is reported to be between sixand seventeen hours in adults and between four and fourteen hours inchildren. This leads to substantial fluctuations in the plasmaconcentration of the drug, especially in chronic administration. Tomaintain reasonably stable plasma concentrations, it is necessary toresort to frequent dosing, and the resulting inconvenience to thepatient often results in lowered compliance with the prescribed dosingregimen. Moreover, widely fluctuating plasma concentrations of the drugmay result in administration of less than therapeutic amounts of thedrug in a conservative dosing regimen, or amounts too large for theparticular patient in an aggressive dosing regimen. The logical solutionto this problem would be to develop sustained release dosage forms thatdecrease the dosing frequency of the compounds.

[0007] However, the pharmacokinetics of valproic acid, and othervalproate compounds, has complicated such development efforts. Therelationship between plasma concentration and clinical response is notwell documented for valproate. One contributing factor is the nonlinear,concentration dependent protein binding of valproate, which affects theclearance of the drug. As the dose of valproate increases, serum levelsrise faster than might be expected since proportionately less of thedose is bound to plasma proteins. For example, because the plasmaprotein binding of valproate is concentration dependant, the freefraction increases from approximately 10% at 40 μg/ml to 18.5% at 130μg/ml.

[0008] These nonlinear kinetics significantly increase the difficulty ofdesigning sustained release dosage forms. Identical doses of thevalproate compound can produce vastly different blood levels dependingupon the rate at which the valproate compound is released from thedosage form.

[0009] Further complicating development efforts is the fact that acorrelation between valproate levels and efficacy is unknown for diseasestates other than epilepsy. For example, therapeutic concentrationsrequired to treat migraine headaches and bipolar disorders have not beenestablished.

[0010] What impact valproate levels play in a number of side effects isalso unknown at the present time. GI irritation is very common inpatients consuming valproate, affecting up to one third of patients. Theincidence increases at elevated doses. It is unknown if this side effectis caused by local irritation within the GI tract or is mediated via thestimulation of a receptor within the central nervous system (and thus isdependant upon plasma valproate levels). Other side effects such asasthenia, dizziness, somnolence, alopecia, and weight gain are quitecommon. It is also unknown if these side effects can be correlated withplasma levels of valproate. A more detailed discussion of valproate sideeffects may be found in PDR supra, page 421-437.

[0011] In spite of the nonlinear kinetics of the compounds, a concertedeffort has been devoted to the discovery of valproate formulations thatwill maintain more constant plasma levels of the drug followingadministration. The ultimate goal of these studies has been thediscovery of a formulation which affords stable plasma levels in aonce-a-day dosing regimen. These efforts fall generally into one of twocategories: (a) finding a form of the active ingredient which is moreslowly released to the body metabolically, and (b) finding a formulationwhich delivers the drug by either a timed- or controlled-releasemechanism.

[0012] U.S. Pat. No. 4,369,172 to Schor, et al. describes, for example,a prolonged release therapeutic composition based on mixtures ofhydroxypropyl methylcellulose, ethyl cellulose and/or sodiumcarboxymethyl cellulose. The patentees provide a long list oftherapeutic agents which they suggest can be incorporated into theformulation including sodium valproate.

[0013] U.S. Pat. No. 4,913,906 to Friedman, et al discloses a controlledrelease dosage form of valproic acid, its amide, or one of its salts oresters in combination with a natural or synthetic polymer, pressed intoa tablet under high pressure.

[0014] U.S. Pat. No. 5,009,897 to Brinker, et al discloses granules,suitable for pressing into tablets, the granules comprising a core ofdivalproex sodium and a coating of a mixture of a polymer andmicrocrystalline cellulose.

[0015] U.S. Pat. No. 5,019,398 to Daste discloses a sustained-releasetablet of divalproex sodium in a matrix of hydroxypropyl methylcelluloseand hydrated silica.

[0016] U.S. Pat. No. 5,055,306 to Barry, et al. discloses aneffervescent or water-dispersible granular sustained release formulationsuitable for use with a variety of therapeutic agents. The granulescomprise a core comprising the active ingredient and at least oneexcipient, and a water insoluble, water-swellable coating comprising acopolymer of ethyl acrylate and methyl methacrylate and a water solublehydroxylated cellulose derivative. The patentees suggest a list oftherapeutic agents which may be used in the formulation of theinvention, including sodium valproate.

[0017] U.S. Pat. No. 5,169,642 to Brinkler, et al. discloses a sustainedrelease dosage form comprising granules of divalproex sodium or amidesor esters of valproic acid coated with a sustained release compositioncomprising ethyl cellulose or a methacrylic methyl ester, a plasticizer,a detackifying agent, and a slow-release polymeric viscosity agent.

[0018] U.S. Pat. No. 5,185,159 to Aubert, et al. discloses a formulationof valproic acid and sodium valproate which is prepared without the useof either a binder or a granulating solvent. The formulation optionallycontains precipitated silica as an anti-sticking or detackifying agent.

[0019] U.S. Pat. No. 5,589,191 to Exigua, et al discloses a slow releasesodium valproate tablet formulation in which the tablets are coated withethyl cellulose containing silicic acid anhydride.

[0020] Published PCT application WO 94/27587 to Ayer, et al. discloses amethod for control of epilepsy by delivering a therapeutic compositionof divalproex sodium in combination with a poly (alkylene oxide).

[0021] Bialer, et al., “Metabolism of Antiepileptic Drugs,” pp. 143-151,R. H. Levy, Ed., Raven Press, New York, 1984; Int. J. Pharmaceutics, 20:53-63 (1984); and Biopharmaceutics and Drug Disposition, 6: 401-411(1985); and Israel J. Med. Sci., 20: 46-49 (1995) report thepharmacokinetic evaluation of several sustained release formulations ofvalproic acid.

[0022] Despite all of these efforts, there remains the need for asustained release formulation of divaproex sodium, and other valproatecompounds, that will permit once-a-day dosing. Further, there remainsthe need for a formulation which will effectively maintain plasmaconcentrations of the drug at more constant levels over a 24 hour dosingperiod (i.e. minimize the variation between peak and trough plasmalevels). Further, sustained release formulations are needed that willdecrease the incidence of side effects associated with valproatetherapy. More specifically, there remains the need to reduce theincidence of nausea, vomiting, asthenia, somnolence, alopecia, weightgain, etc. in patients undergoing valproate therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In the drawings, which form a part of this specification:

[0024]FIG. 1 is a graphical representation of the release of drug fromseveral tests controlled release tablet formulations under in vitroconditions.

[0025]FIG. 2 is a graphical representation of in vitro release of drugfrom two preferred controlled release tablet formulations of theinvention.

[0026]FIG. 3 is a graphical representation of plasma valproate levels oftwo qd (once-a-day) and one bid (twice-a-day) dosage form.

[0027]FIG. 4 is a graphical representation of plasma valproate levels ofa qd (once-a-day) and bid (twice-a-day) dosage form.

SUMMARY OF THE INVENTION

[0028] In accordance with the present invention, a new oral polymericcontrolled release formulation suitable for the once-a-dayadministration of valproate compounds, such as divalproex sodium, hasbeen discovered. This formulation exhibits significant advantages overthe sustained release valproate formulations of the prior art. Thisformulation minimizes the variation between peak and trough plasmalevels of valproate over a 24 hour dosing period. This formulationfollows a zero-order release pattern thus producing essentially flatplasma levels of valproate, once steady-state levels have been achieved.This results in a significantly lower incidence of side effects forpatients consuming such a formulation.

[0029] Peak concentrations of valproate, C_(max), are statisticallysignificantly (p<0.05) below those produced by valproate dosage formssuitable for twice a day administration when measured over a 24 hourperiod. Trough levels of valproate, C_(min), are not statisticallysignificantly different from those obtained with a twice-a-day dosageform (over 24 hours). The extent of absorption, as defined by area underthe curve (“AUC”), is equivalent to those produced by the twice-a-dayvalproate dosage forms (over 24 hours). Such a combination of propertieshas unexpected benefits. It allows therapeutic levels of valproate to bemaintained over a 24 hour dosing period. Further, it has been discoveredthat a significantly lower incidence of side effects has been achievedby this reduction in peak plasma concentration. Gastrointestinal sideeffects, alopecia, and certain CNS side effects have been reduced.

[0030] The once-a-day formulation (“qd”) comprises a valproate compoundthat is in association with at least one pharmaceutically acceptablepolymer. A sufficient quantity of the polymer is utilized, so that uponingestion, steady state plasma valproate levels are obtained having adegree of fluctuation that is lower than that produced by acorresponding twice-a-day valproate dosage form. The qd formulation alsotypically provides for total absorption (AUC) of the valproate compoundthat is at least 80% of that achieved by a daily dose of thecorresponding twice-a-day formulation.

[0031] It is important to emphasize that the formulations of thisinvention are not limited to any one particular mechanism of drugrelease. Given the guidance of this patent application, one skilled inthe art could achieve the enhanced pharmacokinetic and side effectprofile using any oral controlled release polymeric dosage form known inthe art. This includes osmotic pump systems, matrix systems, orreservoir systems.

[0032] A more specific embodiment of this invention is directed to aonce-a-day divalproex sodium dosage form. This formulation has a degreeof fluctuation that is less than that achieved by a divalproex sodiumdelayed release tablet. This qd dosage form also produces totalvalproate absorption that is at least 80% of that achieved by thedivalproex sodium delayed release tablets. Peak steady state serumvalproate levels obtained with the qd dosage form are 10-20% lower thanthat produced by the divalproex sodium delayed release tablets. Troughlevels, which are important in maintaining control of epilepticseizures, are not statistically significantly different from thoseobtained with the divalproex sodium delayed release tablets.

DETAILED DESCRIPTION I. Definitions

[0033] As noted above, the invention relates to new and improved dosageforms of valproic acid and other valproate compounds which disassociatein-vivo to produce a valproate ion. Several valproate compounds arecurrently available commercially in the United States or have beendescribed in the literature.

[0034] One such compound is valproic acid. Valproic acid may berepresented by the following structure:

[0035] Valproic acid is available commercially from Abbott Laboratoriesof Abbott Park, Ill. Methods for its synthesis are described inOberreit, Ber. 29, 1998 (1896) and Keil, Z. Physiol. Chem. 282, 137(1947). It's activity as an antiepileptic compound is described in thePDR, 52nd Edition, page 421, 1998. Upon oral ingestion within thegastrointestinal tract, the acid moiety disassociates to form acarboxylate moiety (i.e. a valproate ion).

[0036] The sodium salt of valproic acid is also known in the art as ananti-epileptic agent. It is also known as sodium valproate and isdescribed in detail in The Merck Index, 12 Edition, page 1691, (1996).Further descriptions may be found in the PDR, 52nd Edition, page 417,(1998).

[0037] Divalproex sodium is effective as an antiepileptic agent and isalso used for migraine and bipolar disorders. Methods for itspreparation may be found in U.S. Pat. No.'s 4,988,731 and 5,212,326, thecontents of both which are hereby incorporated by reference. Likevalproic acid, it also disassociates within the gastrointestinal tractto form a valproate ion.

[0038] In addition to these specific compounds, one of ordinary skill inthe art would readily recognize that the carboxylic moiety of thevalproate compound may be functionalized in a variety of ways. Thisincludes forming compounds which readily metabolize in-vivo to producevalproate, such as valproate amide (valproimide), as well as otherpharmaceutically acceptable amides and esters of the acid (i.e.prodrugs). This also includes forming a variety of pharmaceuticallyacceptable salts.

[0039] Suitable pharmaceutically acceptable basic addition saltsinclude, but are not limited to cations based on alkali metals oralkaline earth metals such as lithium, sodium, potassium, calcium,magnesium and aluminum salts and the like and nontoxic quaternaryammonia and amine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

[0040] Other possible compounds include pharmaceutically acceptableamides and esters. “Pharmaceutically acceptable ester” refers to thoseesters which retain, upon hydrolysis of the ester bond, the biologicaleffectiveness and properties of the carboxylic acid and are notbiologically or otherwise undesirable. For a description ofpharmaceutically acceptable esters as prodrugs, see Bundgaard, E., ed.,(1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam, whichis hereby incorporated by reference. These esters are typically formedfrom the corresponding carboxylic acid and an alcohol. Generally, esterformation can be accomplished via conventional synthetic techniques.(See, e.g., March Advanced Organic Chemistry, 3rd Ed., John Wiley &Sons, New York (1985) p. 1157 and references cited therein, and Mark etal. Encyclopedia of Chemical Technology, John Wiley & Sons, New York(1980)), both of which are hereby incorporated by reference. The alcoholcomponent of the ester will generally comprise (i) a C₂-C₁₂ aliphaticalcohol that can or can not contain one or more double bonds and can orcan not contain branched carbons or (ii) a C₇-C₁₂ aromatic orheteroaromatic alcohols. This invention also contemplates the use ofthose compositions, which are both esters as described herein, and atthe same time are the pharmaceutically acceptable salts thereof.

[0041] “Pharmaceutically acceptable amide” refers to those amides whichretain, upon hydrolysis of the amide bond, the biological effectivenessand properties of the carboxylic acid and are not biologically orotherwise undesirable. For a description of pharmaceutically acceptableamides as prodrugs, see Bundgaard, H., Ed., (1985) Design of Prodrugs,Elsevier Science Publishers, Amsterdam. These amides are typicallyformed from the corresponding carboxylic acid and an amine. Generally,amide formation can be accomplished via conventional synthetictechniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed., JohnWiley & Sons, New York (1985) p. 1152 and Mark et al. Encyclopedia ofChemical Technology, John Wiley & Sons, New York (1980)), both of whichare hereby incorporated by reference. This invention also contemplatesthe use of those compositions, which are both amides as describedherein, and at the same time are the pharmaceutically acceptable saltsthereof.

[0042] As used in this application:

[0043] a) any reference to “valproate” or “valproate compounds” shouldbe construed as including a compound which disassociates within thegastrointestinal tract to produce a valproate ion including, but notlimited to, valproic acid, the sodium salt of valproate, divalproexsodium, any of the various salts of valproic acid described above, andany of the prodrugs of valproic acid described above. Divalproex sodiumis the most preferred valproate compound of the present invention.

[0044] b) “C_(max)” means maximum plasma concentration of the valproateion, produced by the ingestion of the composition of the invention orthe twice-a-day comparator (BID).

[0045] c) “C_(min)” means minimum plasma concentration of the valproateion, produced by the ingestion of the composition of the invention orthe BID comparator.

[0046] d) “C_(avg)” means the average concentration of valproate ionwithin the 24-hour interval produced by the ingestion of the compositionof the invention or the BID comparator. C_(avg) is calculated as AUCover a 24 hour interval divided by 24.

[0047] e) “T_(max)” means time to the maximum observed plasmaconcentration produced by the ingestion of the composition of theinvention or the BID comparator.

[0048] f) “AUC” as used herein, means area under the plasmaconcentration-time curve, as calculated by the trapezoidal rule over thecomplete 24-hour interval for all the formulations.

[0049] g) “Degree of Fluctuation (DFL)” as used herein, is expressed as:DFL=(C_(max)−C_(min))/C_(avg) produced by the ingestion of thecomposition of the invention or the BID comparator.

[0050] h) “Pharmaceutically acceptable” as used herein, means thosesalts/polymers/excipients which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response, andthe like, in keeping with a reasonable benefit/risk ratio, and effectivefor their intended use in the treatment and prophylaxis of migraine,epilepsy, bipolar disorders, etc.

[0051] i) “Side effects” as used herein, means those physiologicaleffects to various systems in the body such as cardiovascular systems,nervous system, digestive system, and body as a whole, which cause painand discomfort to the individual subject, and which are the directresult of the ingestion of the valproate compound.

[0052] j) “decreased incidence of side effects” refers to a reducedincidence of side effects in a patient population, and not to a totalabsence of side effects, when measured in a comparable populationconsuming a valproate dosage form suitable for twice dailyadministration. As is well known to those skilled in the art, evenplacebo dosage forms made of sugar produce some measurable incidence ofside effects. Thus an improved side effect profile must be interpretedin light of the relevant art.

[0053] k) “delayed release divalproex sodium tablets” refers to anenteric coated dosage form containing divalproex sodium intended todelay the release of the medication until the dosage form has passedthrough the stomach.

[0054] l) “bid” refers to the administration of a formulation twiceduring a 24 hour period.

[0055] m) “qd” refers to a dosage form that may be administered onceduring a 24 hour period.

[0056] n) A statistical test is said to be statistically significantwhere the resulting p-value is less than or equal to 0.05, unlessotherwise noted. Equivalence and statistical significance are notsynonymous.

[0057] As used in this application, the terms “C_(min)” and “troughlevels”, should be considered synonyms. Likewise, the terms “C_(max)”and “peak levels” should also be considered synonyms. Any reference to aplasma concentration of valproate ion, and more specifically to anyquantification thereof, such as, for example, C_(min), C_(max), AUC,DFL, etc., should be considered to have been determined at steady statein a fasting population, unless expressly stated otherwise.

II. Pharmacokinetic Profile

[0058] As noted above, the invention resides in the discovery that aformulation having an improved pharmacokinetic profile willsimultaneously accomplish two results. First, it will provide a dosageform of valproate that will maintain therapeutic levels of the valproateion over a 24 hour dosing period, thus providing once daily dosing.Secondly, it will reduce the incidence of side effects associated withvalproate therapy.

[0059] In order to obtain these benefits, it is necessary for theonce-a-day valproate dosage form to achieve certain pharmacokineticparameters, when compared to a bid valproate dosage form. The qd dosageform must reduce peak plasma levels of valproate (C_(max)) withoutsignificantly impacting either trough levels (C_(min)) or the extent ofvalproate absorption (AUC). Further, the qd dosage form will exhibit aDFL that is lower than that exhibited by a corresponding bid valproatedosage form.

[0060] C_(max) for the qd dosage form should be statisticallysignificantly lower than the C_(max) for a bid dosage form of the samevalproate compound, when each is measured at steady state in a fastingpopulation. For example, a once-a-day divalproex sodium dosage form willexhibit a C_(max) that is statistically significantly lower than thatproduced by a divalproex sodium delayed release tablet, when each ismeasured at steady state in a fasting population. Typically, peak plasmalevels of valproate are reduced at least 10%. More typically, these peakplasma levels are reduced up to about 20%. This reduction must beaccomplished with out any significant reduction in trough levels ortotal absorption of valproate.

[0061] C_(min) for the qd dosage form should not be statisticallysignificantly different from that obtained with a bid dosage form of thesame valproate compound, when each is determined at steady state in afasting population. More specifically, C_(min) for a once-day divalproexsodium dosage form should not be statistically significantly differentfrom that obtained with a delayed release divalproex sodium tablet wheneach is measured at steady state in a fasting population. Maintainingcomparable trough levels to those obtained with the prior art bid dosageforms is necessary to maintain the therapeutic efficacy of the valproatecompound. Inadequate trough levels are associated with seizures inepileptic patients.

[0062] In addition to reducing peak valproate levels as described above,it is also important that the total amount of valproate absorbed fromthe qd dosage form not be decreased significantly, when compared to abid dosage form of the same valproate compound when dosed over a 24 hourdosing interval. Total drug absorption is also referred to as AUC (areaunder the curve). Methods for quantifying drug absorption are well knownto those skilled in the art and have been standardized by the UnitedStates Food and Drug Administration atwvvw.fda.gov/cder/guidance/stat-two.pdf, the contents of which arehereby incorporated by reference.

[0063] AUC for the qd dosage form will be equivalent to the AUC of thebid dosage form of the same valproate compound when each is measured atsteady state in a fasting population over a 24 hour period. Equivalenceof a pharmacokinetic parameter refers to the 90% confidence interval ofthe ratio of the central values of the pharmacokinetic parameter of thetest formulation to the reference formulation being contained within0.80 to 1.25. More specifically, the AUC of qd divalproex sodium tabletform will be equivalent to that obtained with a delayed releasedivalproex sodium dosage form when each is determined at steady state ina fasting population over a 24 hour dosing period.

[0064] An AUC of at least 80% should be achieved with the formulationsof this invention, when compared to a bid dosage form over a 24 hourinterval. Values below 80% tend to negatively impact trough levelsleading to sub-therapeutic concentrations of valproate and loss ofepileptic control, etc. AUC's in excess of 125% should also be avoided.Thus with respect to the extent of absorption, the formulations of thisinvention should be considered equivalent to the corresponding bidvalproate dosage form.

[0065] Degree of Fluctuation (“DFL”) is a measurement of how much plasmalevels of a drug vary over the course of a dosing interval. The closerthe DFL is to zero (0), the less variance there is over the course of adosing period. Thus a reduced DFL signifies that the difference in peakand trough plasma levels has been reduced. The DFL for a qd dosage formof this invention will be lower than that of the corresponding biddosage form, for the same valproate compound, when each is evaluated atsteady state in a fasting population. In a more specific embodiment, aqd divalproex sodium dosage form will have a DFL that is lower than thatachieved with a bid delayed release divalproex sodium tablet when eachis evaluated at steady state in a fasting population.

[0066] Despite the numerous therapeutic advantages of valproate therapy,certain patients consuming these medications experience side effects.For example, with divalproex sodium delayed release tablets,approximately 7% of patients report alopecia (hair loss) PDR supra, page435-436. Up to 8% of patients report significant weight gain PDR supra,page 435-436. Such side effects can have disasterous consequences forthe self image of patients, especially for females, or younger patients.It is unknown whether this hair loss or weight gain is associated withobtaining or maintaining certain plasma levels of valproate

[0067] Likewise, up to one-third of patients consuming divalproex sodiumdelayed release tablets report suffering from nausea. While such anevent is certainly not life threatening, it is unpleasant for thepatient. The nausea can lead to non-compliance and subsequent worseningof the patient's disease. Dizziness, tremor, asthenia, somnolence arealso common with valproate therapy. The impact of plasma levels on theseside effects is also unknown. For a more complete discussion ofvalproate side effects, please refer to PDR supra, page 421-437.

[0068] The incidence of these side effects can be reduced significantlyby reducing peak plasma levels of valproate by approximately 10-20%.Further, therapeutic control can be maintained by meeting the DFL,C_(min), and AUC guidelines discussed above. Such a finding was totallyunexpected. The literature clearly documents that the correlationbetween side effects and plasma valproate levels is unknown.

III. Dosage Forms

[0069] As noted above, the benefits of this invention are not limited toa single type of dosage form having a particular mechanism of drugrelease. This enhanced pharmacokinetic profile can be obtained with anyof the oral sustained release dosage forms in use today, following theteachings above.

[0070] As of the filing date of this application, there are three typesof commonly used oral polymeric controlled release dosage forms. Thisincludes matrix systems, osmotic pumps, and membrane controlledtechnology (also referred to as reservoir systems). Each of thesesystems is described in greater detail below. A detailed discussion ofsuch dosage forms may also be found in: (i) Handbook of pharmaceuticalcontrolled release technology, ed. D. L. Wise, Marcel Dekker, Inc. NewYork, N.Y. (2000), and (ii). Treatise on controlled drug delivery,fundamentals, optimization, and applications, ed. A. Kydonieus, MarcelDekker, Inc. New York, N.Y. (1992), the contents of each which is herebyincorporated by reference.

[0071] A) Matrix Systems

[0072] Matrix systems are well known in the art. In a matrix system, thedrug is homogenously dispersed in a polymer in association withconventional excipients. This admixture is typically compressed underpressure to produce a tablet. Drug is released from this tablet bydiffusion and erosion. Matrix systems are described in detail by Wiseand Kydonieus, supra.

[0073] The matrix formulations of this invention comprise a valproatecompound and a pharmaceutically acceptable polymer. Preferably, thevalproate compound is divalproex sodium. The amount of the valproatecompound varies from about 40% to about 80% by weight of the dosageform. Preferably, the dosage form comprises about 45% to about 65% byweight of the valproate compound.

[0074] The pharmaceutically acceptable polymer is a water-solublehydrophilic polymer, or a water insoluble hydrophobic polymer (includingwaxes). Examples of suitable water soluble polymers includepolyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methyl cellulose, vinyl acetate copolymers, polysaccharides(such as alignate, xanthum gum, etc.), polyethylene oxide, methacrylicacid copolymers, maleic anhydride/methyl vinyl ether copolymers andderivatives and mixtures thereof. Examples of suitable water insolublepolymers include acrylates, cellulose derivatives such ethylcellulose orcellulose acetate, polyethylene, methacrylates, acrylic acid copolymersand high molecular weight polyvinylalcohols. Examples of suitable waxesinclude fatty acids and glycerides.

[0075] Preferably, the polymer is selected from hydroxypropyl cellulose,hydroxypropylmethyl cellulose, and methyl cellulose. More preferably,the polymer is hydroxypropylmethyl cellulose. Most preferably, thepolymer is a high viscosity hydroxypropyl-methyl cellulose withviscosity ranging from about 4,000 cps to about 100,000 cps. The mostpreferred high viscosity polymer is a hydroxypropylmethyl cellulose witha viscosity of about 15,000 cps, commercially available under theTradename, Methocel, from The Dow Chemical Company.

[0076] The amount of the polymer in the dosage form generally variesfrom about 20% to about 50% by weight of the composition. Preferably,the amount of polymers varies from about 25% to about 45% by weight ofthe dosage form. Most preferably, the amount of polymer varies fromabout 30% to about 40% by weight of the dosage form.

[0077] The composition of the invention also typically includespharmaceutically acceptable excipients. As is well known to thoseskilled in the art, pharmaceutical excipients are routinely incorporatedinto solid dosage forms. This is done to ease the manufacturing processas well as to improve the performance of the dosage form. Commonexcipients include diluents or bulking agents, lubricants, binders, etc.Such excipients are routinely used in the dosage forms of thisinvention.

[0078] Diluents, or fillers, are added in order to increase the mass ofan individual dose to a size suitable for tablet compression. Suitablediluents include powdered sugar, calcium phosphate, calcium sulfate,microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride,dry starch, sorbitol, etc.

[0079] Lubricants are incorporated into a formulation for a variety ofreasons. They reduce friction between the granulation and die wallduring compression and ejection. This prevents the granulate fromsticking to the tablet punches, facilitates its ejection from the tabletpunches, etc. Examples of suitable lubricants include talc, stearicacid, vegetable oil, calcium stearate, zinc stearate, magnesiumstearate, etc.

[0080] Glidant's are also typically incorporated into the formulation. Aglidant improves the flow characteristics of the granulation. Examplesof suitable glidant's include talc, silicon dioxide, and cornstarch.

[0081] Binders may be incorporated into the formulation. Binders aretypically utilized if the manufacture of the dosage form uses agranulation step. Examples of suitable binders include povidone,polyvinylpyrrolidone, xanthan gum, cellulose gums such ascarboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose,hydroxycellulose, gelatin, starch, and pregelatinized starch.

[0082] Other excipients that may be incorporated into the formulationinclude preservatives, antioxidants, or any other excipient commonlyused in the pharmaceutical industry, etc. The amount of excipients usedin the formulation will correspond to that typically used in a matrixsystem. The total amount of excipients, fillers and extenders, etc.varies from about 10% to about 40% by weight of the dosage form.

[0083] The matrix formulations are generally prepared using standardtechniques well known in the art. Typically, they are prepared by dryblending the polymer, filler, valproate compound, and other excipientsfollowed by granulating the mixture using an alcohol until propergranulation is obtained. The granulation is done by methods known in theart. The wet granules are dried in a fluid bed dryer, sifted and groundto appropriate size. Lubricating agents are mixed with the driedgranulation to obtain the final formulation.

[0084] The compositions of the invention can be administered orally inthe form of tablets, pills, or the granulate may be loose filled intocapsules. The tablets can be prepared by techniques known in the art andcontain a therapeutically useful amount of the valproate compound andsuch excipients as are necessary to form the tablet by such techniques.Tablets and pills can additionally be prepared with enteric coatings andother release-controlling coatings for the purpose of acid protection,easing swallow ability, etc. The coating may be colored with apharmaceutically accepted dye. The amount of dye and other excipients inthe coating liquid may vary and will not impact the performance of theextended release tablets. The coating liquid generally comprises filmforming polymers such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, cellulose esters or ethers (such as cellulose acetate orethylcellulose), an acrylic polymer or a mixture of polymers. Thecoating solution is generally an aqueous solution or an organic solventfurther comprising propylene glycol, sorbitan monoleate, sorbic acid,fillers such as titanium dioxide, a pharmaceutically acceptable dye.

[0085] A particularly preferred matrix system for the extended releaseof the valproate compound there from comprises: from about 50 weightpercent to about 55 weight percent of a valproate compound; from about20 weight percent to about 40 weight percent of hydroxypropylmethylcellulose; from about 5 weight percent to about 15 weight percentof lactose, from about 4 weight percent to about 6 weight percent ofmicrocrystalline cellulose, and from about 1 weight percent to about 5weight percent of silicon dioxide, in which said silicon dioxide has anaverage particle size ranging between about 1 micron and about 10microns; and all weight percentages based upon the total weight of thedosage form.

[0086] This preferred embodiment of the invention also extends a drygranular composition suitable for compressing into a tablet dosage form,the granular composition comprising particles of a size smaller thanabout 1 mm and comprising from about 50 weight percent to about 55weight percent of an active ingredient selected from the groupconsisting of valproic acid, a pharmaceutically acceptable salt or esterof valproic acid, divalproex sodium, and valpromide; from about 20weight percent to about 40 weight percent of hydroxypropylmethylcellulose; from about 5 weight percent to about 15 weight percentof lactose, from about 4 weight percent to about 6 weight percent ofmicrocrystalline cellulose, and from about 1 weight percent to about 5weight percent of silicon dioxide, in which said silicon dioxide has anaverage particle size ranging between about 1 micron and about 10microns; and all weight percentages based upon the total weight of thegranular composition.

[0087] More specifically, a divalproex matrix may be prepared by a) dryblending a mixture of from about 50 weight percent to about 55 weightpercent divalproex sodium, from about 20 weight percent to about 35weight percent hydroxypropylmethyl cellulose, from about 5 weightpercent to about 15 weight percent lactose to form a uniform mixture ofthe dry ingredients; b) wet granulating the dry uniform mixture fromstep a); c) drying and sizing the wet granules from step b) to selectgranules having an average size below 1 mm; d) dry blending the granuleswith from about 4 weight percent to about 6 weight percentmicrocrystalline cellulose, and from about 1 weight percent to about 5weight percent silicon dioxide having an average particle size rangingbetween about 1 micron and about 10 microns; and e) compressing theblended granules of step h) under a force ranging between about 2000 lbf(about 8.9×10³ Newtons) and 10,000 lbf(about 4.45×10⁴ Newtons). In asimilar manner, the microcrystalline cellulose can be dry blended instep (a) with the divalproex sodium, hydroxypropyl methylcellulose andlactose.

[0088] B) Osmotic Pumps

[0089] In an osmotic pump system, a tablet core is encased by asemipermeable membrane having at least one orifice. The semipermeablemembrane is permeable to water, but impermeable to the drug. When thesystem is exposed to body fluids, water will penetrate through thesemipermeable membrane into the tablet core containing osmoticexcipients and the active drug. Osmotic pressure increases within thedosage form and drug is released through the orifice in an attempt toequalize pressure.

[0090] In more complex pumps, the tablet core contains two internalcompartments. The first compartment contains the drug. The secondcompartment contains a polymer which swells on contact with fluid. Afteringestion, this polymer swells into the drug containing compartment at apredetermined rate and forces drug from the dosage form at that rate.Such dosage forms are often used when are zero order release profile isdesired, such as in the instant invention.

[0091] Osmotic pumps are well known in the art and have been describedin the literature. U.S. Pat. Nos. 4,088,864; 4,200,098; and 5,573,776;all of which are hereby incorporated by reference, describe osmoticpumps and methods for their manufacture. Osmotic pumps containingvalproate compounds, such as divalproex sodium, have been described byAyer et al in U.S. Pat. No. 5,980,943, the contents of which are herebyincorporated by reference. One skilled in the art, taking into accountthis applications teachings and those of the '864, '098, '776 and '943patents could produce an osmotic pump matching the pharmacokineticprofile described above.

[0092] As a general guideline, the osmotic pumps of this invention aretypically formed by compressing a tablet of an osmotically active drug(or an osmotically inactive drug in combination with an osmoticallyactive agent or osmagent) and then coating the tablet with asemipermeable membrane which is permeable to an exterior aqueous-basedfluid but impermeable to the passage of drug and/or osmagent. One ormore delivery orifices may be drilled through the semipermeable membranewall. Alternatively, orifice(s) through the wall may be formed in situby incorporating leachable pore forming materials in the wall. Inoperation, the exterior aqueous based fluid is imbibed through thesemipermeable membrane wall and contacts the drug and/or salt to form asolution or suspension of the drug. The drug solution or suspension isthen pumped out through the orifice as fresh fluid is imbibed throughthe semipermeable membrane.

[0093] In a further preferred embodiment, the tablet contains twodistinct compartments. The first compartment contains the drug asdescribed above. The second compartment contains an expandable drivingmember consisting of a layer of a swellable hydrophilic polymer, whichoperates to diminish the volume occupied by the drug, thereby deliveringthe drug from the device at a controlled rate over an extended period oftime.

[0094] Typical materials for the semipermeable membrane includesemipermeable polymers known to the art as osmosis and reverse osmosismembranes, such as cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, agar acetate, amylose triacetate, beta glucan acetate,acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate,polyamides, polyurethanes, sulfonated polystyrenes, cellulose acetatephthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethyl aminoacetate, cellulose acetateethyl carbamate, cellulose acetate chloracetate, cellulose dipalmitate,cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, methyl cellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, cross-linked selectivelysemipermeable polymers formed by the coprecipitation of a polyanion anda polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586;3,541,005; 3,541,006; and 3,546,142, semipermeable polymers as disclosedby Loeb and Sourirajan in U.S. Pat. No. 3,133,132, lightly cross-linkedpolystyrene derivatives, cross-linked poly(sodium styrene sulfonate),poly(vinylbenzyltrimethyl ammonium chloride), cellulose acetate having adegree of substitution up to 1 and an acetyl content up to 50%,cellulose diacetate having a degree of substitution of 1 to 2 and anacetyl content of 21 to 35%, cellulose triacetate having a degree ofsubstitution of 2 to 3 and an acetyl content of 35 to 44.8%, asdisclosed in U.S. Pat. No. 4,160,020.

[0095] The osmotic agent present in the pump, which may be used when thedrug itself is not osmotically active, are osmotically effectivecompounds soluble in the fluid that enters the device, and exhibits anosmotic pressure gradient across the semipermeable wall against theexterior fluid. Osmotically effective osmagents useful for the presentpurpose include magnesium sulfate, calcium sulfate, magnesium chloride,sodium chloride, lithium chloride, potassium sulfate, sodium carbonate,sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate,d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,hydrophilic polymers such as cellulose polymers, mixtures thereof, andthe like. The osmagent is usually present in an excess amount, and itcan be in any physical form, such as particle, powder, granule, and thelike. The osmotic pressure in atmospheres of the osmagents suitable forthe invention will be greater than zero and generally up to about 500atm, or higher.

[0096] The expandable driving member is typically a swellable,hydrophilic polymer which interacts with water and aqueous biologicalfluids and swells or expands to an equilibrium state. The polymersexhibit the ability to swell in water and retain a significant portionof the imbibed water within the polymer structure. The polymers swell orexpand to a very high degree, usually exhibiting a 2 to 50 fold volumeincrease. The polymers can be noncross-linked or cross-linked. Theswellable, hydrophilic polymers are in one presently preferredembodiment lightly cross-linked, such cross-links being formed bycovalent ionic bonds or hydrogen bonds. The polymers can be of plant,animal or synthetic origin. Hydrophilic polymers suitable for thepresent purpose include poly(hydroxy alkyl methacrylate) having amolecular weight of from 30,000 to 5,000,000; kappa carrageenan,polyvinylpyrrolidone having molecular weight of from 10,000 to 360,000;anionic and cationic hydrogels; polyelectrolyte complexes; poly(vinylalcohol) having a low acetate residual, cross-linked with glyoxal,formaldehyde, or glutaraldehyde and having a degree of polymerizationfrom 200 to 30,000; a mixture of methyl cellulose; cross-linked agar andcarboxymethyl cellulose; a water insoluble, water swellable copolymerproduced by forming a dispersion of finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, butylene or isobutylenecross-linked with from 0.001 to about 0.5 moles of saturatedcross-linking agent per mole of maleic anhydride in copolymer; waterswellable polymers of N-vinyl lactams, and the like.

[0097] The expression “orifice” as used herein comprises means andmethods suitable for releasing the drug from the system. The expressionincludes one or more apertures or orifices which have been bored throughthe semipermeable membrane by mechanical procedures. Alternatively itmay be formed by incorporating an erodible element, such as a gelatinplug, in the semipermeable membrane. In cases where the semipermeablemembrane is sufficiently permeable to the passage of drug, the pores inthe membrane may be sufficient to release the agent/drug intherapeutically effective amounts. In such cases, the expression“passageway” refers to the pores within the membrane wall even though nobore or other orifice has been drilled there through. A detaileddescription of osmotic passageways and the maximum and minimumdimensions for a passageway are disclosed in U.S. Pat. Nos. 3,845,770and 3,916,899, the disclosures of which are incorporated herein byreference.

[0098] The osmotic pumps of this invention are manufactured by standardtechniques. For example, in one embodiment, the drug and otheringredients that may be housed in one area of the compartment adjacentto the passageway, are pressed into a solid possessing dimension thatcorresponds to the internal dimensions of the area of the compartmentthe agent will occupy, or the agent and other ingredients and a solventare mixed into a solid or semisolid form by conventional methods such asballmilling, calendaring, stirring or rollmilling, and then pressed intoa preselected shape. Next, a layer of a hydrophilic polymer is placed incontact with the layer of agent in a like manner, and the two layerssurrounded with a semipermeable wall. The layering of agent formulationand hydrophilic polymer can be fabricated by conventional two-layerpress techniques. The wall can be applied by molding, spraying ordipping the pressed shapes into a wall forming material. Another andpresently preferred technique that can be use for applying the wall isthe air suspension procedure. This procedure consists of suspending andtumbling the pressed agent and dry hydrophilic polymer in a current ofair and a wall forming composition until the wall is applied to theagent-hydrophilic polymer composite. The air suspension procedure isdescribed in U.S. Pat. No. 2,799,241; J. Am. Pharm. Assoc., Vol. 48, pp.451-459, (1979). Other standard manufacturing procedures are describedin Modern Plastics Encyclopedia, Vol. 46, pp. 62-70 (1969); and inPharmaceutical Sciences, by Remington, Fourteenth Edition, pp. 1626-1678(1970), published by Mack Publishing Company, Easton, Pa.

[0099] C) Reservoir Polymeric Systems

[0100] Reservoir systems are well known in the art. This technology isalso commonly referred to as microencapsulation, bead technology, orcoated tablets. Small particles of the drug are encapsulated withpharmaceutically acceptable polymer. This polymer, and its relativequantity, offers a predetermined resistance to drug diffusion from thereservoir to the gastrointestinal tract. Thus drug is gradually releasedfrom the beads into the gastrointestinal tract and provides the desiredsustained release of valproate compound.

[0101] These dosage forms are well known in the art. U.S. Pat. Nos.5,286,497 and 5,737,320, both of which are hereby incorporated byreference, describe such formulations and their methods of production.U.S. Pat. Nos. 5,354,556; 4,952,402; and 4,940,588; all of which arehereby incorporated by reference, specifically discuss using suchtechnology to produce sustained release dosage forms of valproatecompounds such as sodium valproate. One skilled in the art, taking intoaccount this applications teachings and those of the '556, '402, '588,'320, and the '497 patents could produce a bead or pellet based dosageform matching the pharmacokinetic profile described above.

[0102] As a general guideline however, a pellet is formed with a core ofa valproate compound, optionally in association with conventionalexcipeints. This core is then coated with one, or more, pharmaceuticallyacceptable polymers. Often, the coating polymer is an admixture of amajor proportion of a pharmaceutically acceptable water insolublepolymer and a minor proportion of a pharmaceutically acceptable watersoluble polymer. The central core may be prepared by a number oftechniques known in the art. Typically the valproate compound is boundto an inert carrier with a conventional binding agent. The inert carrieris typically a starch or sugar sphere. Before the valproate is bound tothe inert carrier, it is typically blended with conventional excipientsto expedite its handling and to improve the properties of the finaldosage form. These excipients are identical to those described above forthe matrix systems. The quantity of these excipients can vary widely,but will be used in conventional amounts. The central core is thenproduced by utilizing a binding agent to attach the powdered valproateblend to the solid carrier. This can be accomplished by means known inthe art for producing pharmaceutical beads. Suitable means includeutilization of a conventional coating pan, an automatic coating machine,or a rotogranulator. The production of these central cores is describedin more detail in Pharmaceutical Pelletization Technology, ed. I.Ghebre-Sellassie, Marcel Dekker, Inc. New York, N.Y. (1989) which ishereby incorporated by reference.

[0103] The second major component of the beads is the polymeric coating.As noted above, the polymeric coating is responsible for giving thebeads their sustained release characteristics. The polymeric coating maybe applied to the central core using methods and techniques known in theart. Examples of suitable coating devices include fluid bed coaters, pancoaters, etc. The application techniques are described in more detailin: 1) Aqueous polymeric coatings for pharmaceutical dosage forms, ed.J. W. McGinity, Marcel Dekker, Inc. New York, N.Y. (1997); and 2)Pharmaceutical Dosage Forms: Tablets Vol. 3. ed. H. A. Lieberman, L.Lachman and J. B. Schwartz, Marcel Dekker, Inc. New York, N.Y. pp.77-287, (1990), the contents of each which are hereby incorporated byreference.

[0104] Examples of suitable polymers include ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,cellulose acetate phthalate, cellulose triacetate, poly(methylmethacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) lowdensity, poly(ethylene) high density, poly(propylene), poly(ethyleneoxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether),poly(vinyl acetate), poly(vinyl chloride) or polyurethane or mixturesthereof.

[0105] Once the beads have been prepared, they may be filled intocapsules as is known in the art. Alternately, they may be pressed intotablets using techniques conventional in the art.

[0106] The following examples are presented in order to furtherillustrate the invention. While all of the examples specifically relateto matrix dosage forms, their relevance extends to any of the dosageforms described above. One skilled in the art could use their teachingsto prepare reservoir systems or osmotic pumps having the pharnacokineticprofile described above.

EXAMPLES Example 1

[0107] The following example provides a summary of the experimental workculminating in the formulation of the present invention.

[0108] One gram tablets containing 538 mg of divalproex sodium,magnesium stearate, dicalcium phosphate, microcrystalline cellulose(Avicel®, FMC Corporation, Philadelphia, Pa., USA) and/or lactose andvarious hydrophilic polymers were prepared. Hydrophilic polymers testedincluded hydroxypropyl methylcellulose, methylcellulose (Methocel®grades K100LVP CR, K4MP CR, K15MP CR and K100MP CR, Dow Chemical,Midland, Mich.; USA); hydroxypropyl cellulose (Klucel® LF, Hercules,Inc., Wilmington, Del.; USA); and alginate (Keltone® grades LVCR andHVCR, Kelco Co., San Diego, Calif.; USA).

[0109] Bulk drug was milled prior to use and was sized to pass a 40 meshsieve (0.42 mm nominal mesh opening). The milled and sieved bulk drugwas dry-mixed with polymer and excipients in a Collette Gral 10 highshear mixer for 5 min at a high chopper speed of 3000 rpm and impellerspeed of 200 rpm. Granules were prepared by adding 70 ml/kg ofgranulation fluid (water or water/ethanol mixtures) to thepolymer/drug/excipient powder mixture over a 1-2 minute period at highchopper speed of 3000 rpm and impeller speed of 500 rpm. Additionalfluid of 10-165 ml was added in one step as needed in order to reachgranulation end-point. Total granulation time ranged from 2-18 min.

[0110] Tablet matrix ingredients included microcrystalline cellulose,lactose, magnesium stearate, and silicon dioxide. The resulting granuleswere tray dried at 50° C.-55° C. overnight under reduced pressure. Thedried granules were mixed with lubricant (magnesium stearate) in a bagand then passed through a 20 mesh (0.84 mm nominal opening) sieve.Tablets weighing 1 g were pressed in a Model C Carver Press tabletingmachine using a 0.747 inch (1.9 cm)×0.360 inch (0.91 cm) ovaloid die ata compression force between about 2000 lbf (about 8.9×10³ Newtons) andabout 10,000 lbf (about 4.45×10⁴ Newtons), preferably between about 2300lbf (1.02×10⁴ Newtons) to about 5000 lbf (2.25×10⁴ Newtons). The tabletcompositions are presented in Table 1. TABLE 1 Test Divalproex MatrixTablet Formulations Ingredient¹ A B C D E F G H I Divalproex 50 50 50 5050 53.8 53.8 53.8 53.8 sodium Methocel ® 18 20 — — — — — — 10 K100LVPCRMethocel ®  8 — — — — — — — — K4MPCR Klucel ® LF — 20 — — — — — — —Keltone ® — — 30 — — — — — — HVCR Methocel ® — — — — 30 26 35 — 16K15MPCR Methocel ® — — — 15 — — — 30 — K100MPCR Lactose 23 9.5 9.5 29.514.5 14.7 5.7 10.7 14.7 Avicel ® —  0  5 5 5 5 5 5 5 PH101 PVP² — —  5 —— — — — — Magnesium  1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Stearate

Initial Formulation Screening

[0111] Initial screening of the matrix tablet formulations was performedusing a number of tests. Tablet hardness for each formulation wasmeasured using a Model VK2000 VanKel tablet hardness analyzer andrecorded in units of kiloPounds (kP) as the average of ten trials.

[0112] Friability of the tablets were tested by rotating the tabletssamples 100 times using a Erweka TA friabilator. Friability of tabletsfor each formulation were calculated based on the weight loss of thetablets in this test.

[0113] Bulk density of the formulation granules was measured bycarefully filling a glass graduated cylinder to the 100 ml mark. Tapdensity was determined following 100 taps of the filled cylinder.

[0114] Determination of granule size distribution was performed bycollecting granules larger than 140 mesh (about 0.105 mm nominal meshopening) and 40 mesh (about 0.42 mm nominal mesh opening) for evaluationof the percentage of fines and large granules.

[0115] In vitro dissolution tests were conducted using Apparatus IIdescribed in the United State Pharmacopeia XXI/National Formulary XVI.Samples aliquots of 1.5 ml were withdrawn and filtered through a 0.45 μmfilter and assayed by TDX® fluorescent polarization immunoassay. Uponwithdrawal of each sample, an equal volume of medium was added to thetest mixture to maintain constant volume. The test conditions were asfollows: Apparatus USP II, paddle Medium 1 M HCl for one hour; remainingtime pH 6.8 buffer Volume of medium 900 ml Temperature 37° C. ± 0.5° C.Paddle speed 100 rpm Sampling volume 1.5 ml Sampling times 0, 0.5, 1, 2,4 ,6, 8, 13, 24 hours

[0116] The results of these tests are presented in Table 2.

[0117] Based upon these initial studies, and the data appearing in Table2 above, the following conclusions were drawn:

[0118] (1) Effects on tablet hardness: The use of ethanol as agranulation fluid tends to increase tablet hardness. There is a stronginteraction between ethanol and particle size of the bulk drug. Theincrease in hardness was only observed for formulations containing drugof larger particle size. The opposite effect was found for drug ofsmaller particle size.

[0119] (2) Effects on friability: The use of drug having a smallparticle size reduced friability. However, this effect was significantonly for formulations using water as granulation fluid.

[0120] (3) Effects on density: The use of ethanol as a granulation fluidwas shown to decrease the density of the granules. However, significantinteractions of ethanol with the use of Klucel®, and of ethanol withdrug particle size were observed. Ethanol decreased the density only offormulations containing drug of larger particle size and/or formulationswithout Klucel® present. The opposite effects were found forformulations containing smaller drug particles and/or Klucel®. The sameconclusions were obtained with either tap or bulk density as response.

[0121] (4) Effects on size of granules: More granules of larger sizewere obtained with the use of drug having a larger particle size.Moreover, interaction between ethanol and Klucel® was found to besignificant i.e. use of ethanol tends to generate larger granules whenthere is no Klucel® present in the formulation. No effect was observedfor formulations containing 4% Klucel®. Factors that showed significantinfluences on the percentage of fines in the granules included ethanol,drug particle size, and their interaction. Using smaller drug particlestended to yield more fines in the granules. More fines were generatedwhen ethanol was used as a granulation fluid. The effect of ethanol wasmost significant for formulations containing drug of a small particlesize.

[0122] (5) Effects on granulation fluid volume: In order to obtaingranulation end-point, more fluid volume was needed for formulationscontaining either drug of a smaller particle size or with the use ofethanol as granulation fluid.

[0123] (6) In vitro drug release: In vitro percent release of valproicacid from controlled-release tablets are shown in FIG. 1. The differencein release profiles among formulations was small. In the study, percentrelease at 8 hours (Q_(8hr)) was used to represent release rate for dataanalysis. It was found that the use of Klucel® or drug of a largerparticle size in the formulation resulted in an increase in releaserate. Similar results were obtained when Q_(10hr) or Q_(24hr) was usedto estimate the release rate.

[0124] Formulations containing high load and high viscosity grades ofpolymers often showed poor compressibility. This is believed to be theresult of the increase in polymer order and elasticity with increasingmolecular weight. Hardness of the tablets remained almost unchangedunder compression forces ranging from about 3000 lb (1.3×10⁴ Newtons) toabout 10,000 lb (4.45×10⁴ Newtons). TABLE 2 Granulating Tap Bulk %Granule Form- Fluid Hardness Friability Density Density Size Q_(8 hr)ulation Volume (kP) (% Loss) (g/ml) (g/ml) >40 Mesh Fines¹ (%)² A 10011.9 0.049 0.504 0.429 22.6 6.1 27.6 B 80 7.2 0.16 0.515 0.438 31.3 9.829.0 C 115 12.2 0.025 0.459 0.39 30.2 3.3 28.6 D 80 8.4 0.162 0.4590.406 38.2 6.6 30.4 E 235 10.4 0.060 0.599 0.509 21.5 40.7 27.0 F 11012.2 0.006 0.400 0.340 49.2 1.8 28.0 G 200 9.4 0.085 0.596 0.506 24.029.7 29.7 H 150 12.9 0.142 0.593 0.504 35.0 22.8 30.0 I 130 9.5 0.0150.475 0.404 33.8 1.2 28.8

[0125] In order to increase the hardness of tablets, microcrystallinecellulose and colloidal silicon dioxide were tested by externally addingsmall amounts to the granules at levels of 1-5%. Table 3 shows theresults from the test. It was found that external addition of smallamounts of microcrystalline cellulose or colloidal silicon dioxidesignificantly increased tablet hardness. TABLE 3 Effect of ExternalAddition of Microcrystalline Cellulose or Silicon Dioxide Hardness TestHardness Formulation Additive (kP) Ia None  6.2 Ib 5% Avicel ®  9.6 Ic5% Avicel ® and 1% silicon 13.8 dioxide¹ Iia None — Iib 1% Silicondioxide¹ 10.9 Iic 5% Avicel ® and 1% silicon 14.4 dioxide¹ IIIa None 5.8 IIIb 1% Silicon dioxide¹ 10.8 IIIc 5% Avicel ® and 1% silicon 14.8dioxide¹

[0126] As shown by the data in Table 3, the addition of either 1%silicon dioxide or 5% microcrystalline cellulose to the hydrophilicmatrix formulations of the invention almost doubled tablet hardness,while adding both resulted in a greater than doubling of tablethardness. However, although the results shown above demonstratedimprovement of tablet hardness by the combined use of the externaladdition of Avicel® microcrystalline cellulose and Cab-o-sil® silicondioxide, problems of sticking and relatively low density persisted. Thelow bulk density (i.e. 40 g/l) of the small particle size Cab-O-Sil®fumed silica led to the problem of not being able to load sufficientmaterial into the tablet die.

[0127] In response to this problem, a different silicon dioxide having alarger average particle size ranging from about 1 micron to about 10microns, preferably ranging between about 2 microns to about 5 microns,and most preferably about 2-3 microns was used. One such material isavailable as Syloid®244, available from W. R. Grace, Lexington, Mass.,USA. When this material was used, initially intended as a de-tackifyingand hardening agent for tableting, a surprising and unexpected benefitwas conferred upon the formulation, as shown below. The material wasadded “externally” to the formulation: that is, the active ingredient,polymer(s) and excipients were dry blended, wet granulated, and thendried and sized. The silicon dioxide was then added to the granularformulation and the resulting mixture blended prior to pressing intotablets.

[0128] On the basis of the above findings, preferred tablet formulationswere chosen for an in vivo absorption study in healthy human subjects.The ingredients of the formulations and in vitro release rates are shownin Table 4 and FIG. 2, respectively. The formulations were designed tohave different release rates by using high viscosity HPMC alone orblended with low viscosity HPMC. The target in vitro release rates werechosen to release drug in vivo for 16-20 hours. TABLE 4 PreferredControlled Release Formulations of the Invention Preferred PreferredIngredient Formulation A Formulation B Divalproex sodium  53.82%² 53.82%(milled)¹ Hydroxypropyl    8%   30% methylcellulose (Methocel ® K15M,CR) Methyl cellulose   18% — (Methocel ® K100L, CR) Anhydrous lactose12.18%  8.18% Microcrystalline cellulose    5%    5% (Avicel ® PH 101)Silicon dioxide    3%    3% (Average particle size 1 m <> 10 μm)(Syloid ® 244) Total tablet weight 1 g 1 g

[0129] The controlled release tablet formulations of the presentinvention thus provide an effective delivery system for the once dailyadministration of valproic acid (divalproex sodium) to patients in needof such treatment. The formulations of the invention providesubstantially level plasma concentrations of valproic acid fallingwithin the therapeutic range of the drug over a period which permitsadministration once daily.

Example 2

[0130] This Example illustrate the manufacture of a preferred dosageform of the present invention at a larger scale.

[0131] Divalproex sodium was milled through a 0.040″ band with impactforward (flat edge) using a Fluid Air Mill operating at 50-75 rpm feedrate and 3500 rpm mill speed. 81 kg of milled drug was vacuum loadeddirectly into the Collette Gral-600 high shear mixer and mixed with 12.3kg of lactose, 7.5 kg of microcrystalline cellulose and 45 kg ofhydroxypropylmethycellulos for 5 minutes. The mixture of drug andexcipients was granulated using 18 kg of purified water for a total of 7minutes and dried in a fluid bed dryer until the average moisturecontent of the granules, measured by a gravimetric test, is below thein-process control limit of 1.0% w/w. The dried granules are sized usinga speed sifter and the oversize granules are milled through a 0.078″band with impact forward (flat edge) using a Fluid Air Mill operating at50 rpm feed rate and 3500 rpm mill rate. The two fractions of granulesare then recombined and blended with 4.5 kg of silicon dioxide in atwin-shell blender. The blended mixture is compressed into 1.00 gramtablets with approximately 0-12 kN precompression and 24 kN maincompression force using a rotary tableting machine (Fette 2090)operating at 35-50 rpm.

Example 3 Multiple Dose Study

[0132] The bioavailability and plasma concentration versus time profileof valproate from an oral extended-release tablet formulation ofdivalproex sodium (made as in Example 2) determined under fasting andnonfasting conditions was compared to those of a commercially availableenteric coated divalproex sodium delayed-release tablet formulation(Depakote®, Abbott Laboratories; reference) determined under fastingconditions in healthy subjects. The study was conducted according to amultiple-dose, open-label, three-period, randomized, complete crossoverdesign. In each period, a six-day regimen was administered with aminimum of 16 days separating the first doses of consecutive periods.The three regimens were: Regimen A: Extended-release formulation 1000 mgq24h administered under fasting conditions (test/invention) Regimen B:Extended-release formulation 1000 mg q24h administered 30 minutes afterbreakfast was served (test/invention) Regimen C: Depakote enteric coatedtablet 500 mg q12h administered under fasting conditions (reference/bidcomparator)

[0133] A schedule of the doses and meal times for the three regimensfollows. TABLE 5 Regimen Formulation Time of Dose Breakfast Lunch DinnerSnack A Test ER 6:00 a.m. 8:00 a.m. 12 N 8:00 pm 10:30 pm B Test ER 6:00a.m. 5:30 a.m. 12 N 8:00 pm 10:30 pm C Reference DR 6:00 a.m. 8:00 a.m.12 N 8:00 pm 10:30 pm 6:00 p.m.

[0134] Fourteen healthy adult subjects (11 male and 3 female subjects)completed all phases of the study. The mean age was 27 years (range19-51 years), mean height was 69 inches (range 63-74 inches) and weightwas 161 pounds (range 120-200 pounds).

[0135] Blood samples (7 mL) were collected at 0, 12, 24, 36, 48, 60, 72,84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132,133, 134, 135, 136.5, 138, 139.5, 141, 142.5 and 144 hours after thefirst dose of each period. Plasma samples were analyzed for valproicacid using a validated gas-liquid chromatographic method with flameionization detection at Oneida Research Services, Inc., Whitesboro, N.Y.

Pharmacokinetic and Statistical Analyses

[0136] Pharmacokinetic parameters were estimated by noncompartmentaltechniques. For Day 6 data, these included C_(max), T_(max), C_(min),AUC₀₋₂₄, and degree of fluctuation (DFL). If C_(max) for the referenceoccurred after the second dose of Day 6, T_(max) was taken to be thetime since the second dose rather than the time from the first dose.

[0137] Analyses of variance (ANOVAs) appropriate for crossover modelswere performed for T_(max), DFL, and for the natural logarithms ofC_(min), C_(max), and AUC₀₋₂₄. Within the framework of the ANOVA, theregimens were compared pair-wise, each comparison done by a test atsignificance level of 0.05. Equivalence of the two formulations withrespect to AUC was addressed by performing the two one-sided testsprocedure at significance level 0.05 within the framework of the ANOVAon the logarithm of AUC. As a further aid for assessing thecharacteristics of the ER formulation, 95% confidence intervals for theratios of the ER formulation central values to the reference regimencentral value were obtained from the ANOVAs for logarithms of C_(min)and C_(max). In addition, a two one-sided tests procedure was carriedout to compare the fasting and nonfasting extended-release formulationregimens.

[0138] The mean valproic acid plasma concentration-time profiles for thethree regimens are shown in FIG. 3.

[0139] The pharmacokinetic results for Day 6 of each regimen aresummarized in the following Table 6. TABLE 6 Mean (Standard Deviation),n = 14 T_(max) C_(max) C_(min) AUC₀₋₂₄ Regimen (hr) (μg/mL) (μg/mL) (μg· hr/mL) DFL A 13.6 (6.3)* 80.5 (18.6)* 48.2 (17.0) 1592 (402) 0.523(0.231) B 15.9 (4.5)* 85.0 (12.5)* 55.1 (13.3) 1709 (276) 0.432 (0.127)*C  3.6 (0.9) 99.4 (15.7) 54.1 (13.1) 1789 (332) 0.623 (0.160)

[0140] The mean T_(max) for Regimens A and B were about three-foldlonger than that of Regimen C. The differences in T_(max) betweenRegimens A and C and between B and C were statistically significant.Regimens A and B tended to have lower C_(max) than that of Regimen C,and these differences were statistically significant. The regimens didnot differ statistically significantly with respect to C_(min). The meanDFL for both ER Regimens A and B was lower than that of the reference,and the difference between Regimen B and the reference was statisticallysignificant.

[0141] The 95% confidence intervals for bioavailability of the ERregimens relative to the reference for C_(max) and C_(min) are givenbelow. The point estimate for the ratio of the central values for bothC_(max) and C_(min) for Regimen A, and C_(max) for Regimen B, were lowerthan 1.0. The point estimate of the ratio for C_(min) for Regimen B wasapproximately unity. TABLE 7 Relative Bioavailability C_(max) C_(min)95% 95% Regimen Point Confidence Point Confidence Test ReferenceEstimate Interval Estimate Interval A C 0.811 0.742-0.887 0.8470.672-1.067 B C 0.861 0.788-0.941 1.026 0.814-1.293

[0142] The results for the two one-sided tests procedure for equivalenceassessment of the regimens via a 90% confidence interval based on thenatural logarithm of AUC₀₋₂₄ are given below. TABLE 8 Two One-SidedTests Procedure for Equivalence Assessment, Day 6 AUC RelativeBioavailability 90% Confidence Test Reference Point Estimate Interval AC 0.891 0.817-0.971 B C 0.970 0.890-1.058 A B 0.918 0.842-1.001

[0143] The 90% confidence intervals for AUC on Day 6 for the test ERformulation administered under fasting (A) and nonfasting (B) conditionsversus the reference fasting (C), both satisfied the 0.80-1.25 criterionfor equivalence. Additionally, the 90% confidence interval for the ratioof central values of AUC for the test ER formulation fasting:nonfastingregimens also satisfied the equivalence criterion.

[0144] The extended-release formulation performs well. Theextended-release regimens are equivalent to the reference regimen withrespect to extent of absorption as characterized by AUC. The two testregimens did not differ statistically significantly from the referenceregimen with respect to C_(min). The lower C_(max) and later T_(max)central values of the extended-release regimens compared the referenceregimen suggest that the ER formulation provides extended release ofvalproic acid in vivo under fasting and nonfasting conditions. The meanDFL for the extended-release formulation administered under nonfastingconditions is lower (˜31%) than that of the reference regimen (observedmeans of 0.432 and 0.623, p<0.05). The mean DFL for the extended-releaseformulation administered under fasting conditions was also lower (−16%)than that of the reference regimen although statistical significance wasnot attained (observed means of 0.523 and 0.623, p=0.126).

Example 4 Multiple Dose Study

[0145] The bioavailability and plasma concentration-time profile ofvalproic acid from a new oral extended-release tablet formulation ofdivalproex sodium (invention, made as in Example 2) was compared to thatfrom the currently marketed divalproex sodium enteric-coateddelayed-release tablet (Depakote® Abbott Laboratories; reference) undermultiple-dose conditions.

[0146] Sixteen subjects enrolled in the study. They had a mean age of 34years (range 19-55 years), mean height of 69 inches (range 65-75inches), and mean weight of 180 pounds (range 148-209 pounds). This wasa multiple-dose, open-label, 2-period, crossover study with no washoutbetween periods in healthy adult male and female subjects comparing theextended-release (ER/invention) test formulation (2×500 mg qd) with thedelayed-release (DR/bid/prior art) Depakote enteric-coated tablet (500mg ql 2 h) as the reference. In one part of the study (Groups I and II),4 subjects started on the ER test tablet in the morning and switchedover to the 500 mg DR tablet bid on Day 7 (end of Period 1) andcontinued on it through Day 12 (Period 2). The other four subjects(Group II) started with the DR tablet and switched over to the ER testtablet in the morning of Day 7 and continued through Day 12. The secondpart of the study (Groups III and IV) was a repeat of the first partexcept that the test formulation was given in the evening instead of inthe morning. The ER formulation was administered after a meal, and theDR tablet was given under fasting conditions.

[0147] A schematic of the formulations administered and the meal timesfollows. TABLE 9 Formulation Time of Dose Breakfast Lunch Dinner SnackMorning Dose for ER Formulations ER 6 am 5:30 am 12 N 5:30 pm 10:30 pmDR 6 am, 6 pm 8:00 am 12 N 8:00 pm 10:30 pm Evening Dose for ERFormulations ER 6 pm 5:30 am 12 N 5:30 pm 10:30 pm DR 6 pm, 6 am 8:00 am12 N 8:00 pm 10:30 pm

[0148] Regimens: The regimens administered were as follows.

[0149] A: Divalproex sodium extended-release tablets, 500 mg valproicacid equivalents; 2×500 mg tablets once every 24 hours starting with amorning dose. (invention)

[0150] B: Divalproex sodium enteric-coated delayed-release tablets (sameas Depakote, Abbott Laboratories, reference); one 500 mg tablet onceevery 12 hours starting with a morning dose.

[0151] C: Divalproex sodium extended-release tablets, 500 mg valproicacid equivalents; 2×500 mg tablets once every 24 hours starting with anevening dose. (invention)

[0152] D: Divalproex sodium enteric-coated delayed-release tablets (sameas Depakote, Abbott Laboratories, reference; one 500 mg tablet onceevery 12 hours starting with an evening dose.

[0153] Blood samples (7 mL) were taken at 0, 12, 24, 36, 48, 60, 72, 84,96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133,134, 135, 136.5, 138, 139.5, 141, 142.5 and 144 hours from the firstdose of each period. Blood samples were taken on the same schedule forGroups III and IV except that they were 12 hours later than for Groups Iand II (i.e., first blood sample at 6 p.m. instead of 6 a.m.). Plasmasamples were analyzed for valproic acid using a validated gas-liquidchromatographic method with flame ionization detection at OneidaLaboratories, New York.

Pharmacokinetic and Statistical Analyses

[0154] Pharmacokinetic parameters were estimated by noncompartmentaltechniques. For Day 6 and 12 data, C_(max), T_(max), C_(min), AUC₀₋₂₄and DFL were calculated. If T_(max) occurred after the second dose ofDay 6 or 12, T_(max) was taken to be the time since the second doserather than the time from the first dose.

[0155] Analyses of variance (ANOVAs) were performed for T_(max), DFL,and for the natural logarithms of C_(min), C_(max), and AUC₀₋₂₄. Themodel had effects for time (whether subject received ER formulation inmorning or evening), formulation sequence, subjects nested within timeby formulation sequence, formulation period, and the interaction of timewith each of formulation sequence, formulation and period. Subjecteffects were random and all other effects were fixed. Equivalence of thetwo formulations with respect to AUC was addressed by performing the twoone-sided tests procedure within the framework of the ANOVA on thelogarithm of AUC. This confidence interval for relative bioavailabilitywas obtained by exponentiating the endpoints of a 90% confidenceinterval for the difference of logarithm means (difference offormulation main effects). As a further aid for assessing thecharacteristics of the ER formulation, 95% confidence intervals forbioavailability relative to that of the reference formulation wereobtained from the ANOVAs for logarithms of C_(min) and C_(max).

[0156] The mean plasma valproic acid concentrations followingadministration of the 1000 mg test formulation once every 24 hours(Regimens A and C) or the 500 mg reference formulation once every 12hours (Regimens B and D) for Days 6 and 12 are shown in FIG. 4.

[0157] The pharmacokinetic results for Day 6 of each regimen aresummarized in the following table. TABLE 10 Mean (% Coefficient ofVariation) C_(max) C_(min) AUC₀₋₂₄ Regimen (μg/mL) (μg/mL) (μg · hr/mL)DFL ER formulation in morning (n = 8) A 0-24 hr  87 (17.3) 55.5 (38.7)1771 (22.8) 0.46 (55.9) B 0-24 hr 102 (10.5) 53.3 (26.2) 1798 (16.6)0.67 (31.2) ER formulation in evening (n = 8) C 0-24 hr  85 (10.0) 57.4(14.9) 1728 (12.5) 0.39 (19.7) D 0-24 hr  98 (10.2) 54.7 (13.9) 1747(10.5) 0.60 (12.3) All groups combined A and C 0-24 hr  86 (13.8) 56.4(28.1) 1749 (17.9) 0.42 (44.3) B and D 0-24 hr 100 (10.3) 54.0 (20.2)1773 (13.6) 0.64 (24.8)

[0158] There were no statistically significant differences in thepharmacokinetic results between subjects who received the ER formulationin the morning and those who received the ER formulation in the evening.Hence, the conclusions are based on the combined data of the groups.

[0159] The mean DFL of the ER formulation was statisticallysignificantly lower than that of the reference. The two formulationsdiffered statistically significantly with respect to C_(max), but notwith respect to C_(min) and AUC. For C_(max) and C_(min), the 95%confidence interval for bioavailability of the ER formulation relativeto that of the reference was 0.80 to 0.91 and 0.89 to 1.18,respectively. The 90% confidence interval by which the two one- sidedtests procedure was performed for AUC was 0.924 to 1.041, being entirelywithin the equivalence range of 0.80 to 1.25.

[0160] Mean C_(max) for the test formulation on Day 6 for both periods,when the plasma valproic acid concentrations were characterized, waslower than the reference formulation and was statistically significantlydifferent. Mean AUC₀₋₂₄ for Day 6 of each period was not significantlydifferent between the test and reference formulations. Relativebioavailability based on the ratio (test:reference) of mean logarithm ofAUC₀₋₂₄ (90% confidence interval) was 0.981 (0.924 to 1.041). The degreeof fluctuation was statistically significantly smaller for the testformulation (0.42) than for the reference (0.64). The resultsdemonstrate the extended-release characteristics of the test formulationand its similarity in bioavailability based on AUC when compared to thereference formulation.

Example 5

[0161] Based on the results of one multicenter, randomized,double-blind, placebo-controlled clinical trial, the formulation ofExample 2 (hereinafter “Depakote ER”) was well tolerated in theprophylactic treatment of migraine headache. Of the 122 patients exposedto Depakote ER in the placebo-controlled study, 8% discontinued foradverse events, compared to 9% for the 115 placebo patients.

[0162] a) Invention

[0163] The study below describes the side effect profile of a qddivalproex sodium dosage form according to this invention.

[0164] Table 11 includes those adverse events reported for patients inthe placebo-controlled trial where the incidence rate in the DepakoteER-treated group was greater than 5% and was greater than that forplacebo patients. TABLE 11 Adverse Events Reported by >5% of DepakoteExtended Release (ER/Invention) Patients During the MigrainePlacebo-Extended Trial with a Greater Incidence than Patients TakingPlacebo¹ Body System Depakote ER Placebo Event (N = 122) (N = 115)Gastrointestinal Nausea 15% 9% Dyspepsia 7% 4% Diarrhea 7% 3% Vomiting7% 2% Abdominal Pain 7% 5% Nervous System Somnolence 7% 2% OtherInfection 15% 14%

[0165] The following additional adverse events were reported by greaterthan 1% but not more than 5% of Depakote ER-treated patients and with agreater incidence than placebo in the placebo-controlled clinical trialfor migraine prophylaxis:

[0166] Body as a Whole: Accidental injury, viral infection.

[0167] Digestive System: Increased appetite, tooth disorder.

[0168] Metabolic and Nutritional Disorders: Edema, weight gain.

[0169] Nervous System: Abnormal gait, dizziness, hypertonia, insomnia,nervousness, tremor, vertigo.

[0170] Respiratory System: Pharyngitis, rhinitis.

[0171] Skin and Appendages: Rash.

[0172] Special Senses: Tinnitus.

[0173] b) Prior Art

[0174] The study below describes the side effect profile of Depakote DR.

[0175] Based on two placebo-controlled clinical trials and their longterm extension, Depakote DR tablets were generally well tolerated withmost adverse events rated as mild to moderate in severity. Of the 202patients exposed to Depakote DR tablets in the placebo-controlledtrials, 17% discontinued for intolerance. This is compared to a rate of5% for the 81 placebo patients. The adverse events reported as theprimary reason for discontinuation by greater than or equal to 1% of 248Depakote DR-treated patients were alopecia (6%), nausea and/or vomiting(5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOTand/or SGPT (1%), and depression (1%).

[0176] Table 12 includes those adverse events reported for patients inthe placebo-controlled trials where the incidence rate in the DepakoteDR-treated group was greater than 5% and was greater than that forplacebo patients. TABLE 12 Adverse Events Reported by >5% of DepakoteDelayed Release (DR/prior art) Patients During Migraine Placebo-ExtendedTrials with a Greater Incidence than Patients Taking Placebo¹ BodySystem Depakote DR Placebo Event (N = 202) (N = 81) GastrointestinalSystem Nausea 31% 10% Dyspepsia 13% 9% Diarrhea 12% 7% Vomiting 11% 1%Abdominal Pain 9% 4% Increased Appetite 6% 4% Nervous System Asthenia20% 9% Somnolence 17% 5% Dizziness 12% 6% Tremor 9% 0% Other Weight Gain8% 2% Back Pain 8% 6% Alopecia 7% 1%

[0177] The following additional adverse events not referred to abovewere reported by greater than 1% but not more than 5% of DepakoteDR-treated patients and with a greater incidence than placebo in theplacebo-controlled clinical trials:

[0178] Body as a Whole: Chest pain.

[0179] Cardiovascular System: Vasodilatation.

[0180] Digestive System: Constipation, dry mouth, flatulence,stomatitis.

[0181] Hemic and Lymphatic System: Ecchymosis.

[0182] Metabolic and Nutritional Disorders: Peripheral edema.

[0183] Musculoskeletal System: Leg cramps.

[0184] Nervous System: Abnormal dreams, confusion, paresthesia, speechdisorder, thinking abnormalities.

[0185] Respiratory System: Dyspnea, sinusitis.

[0186] Skin and Appendages: Pruritus.

[0187] Urogenital System: Metrorrhagia.

[0188] Although the safety of ER and DR formulations were not assessedin the same study, a cross-study comparison of the data presented inTables 11 and 12 suggest that the rate of adverse events were similar inthe placebo-treated patients of the three well-controlled randomizedstudies. It is evident from Tables 11 and 12 that while the adverseevents in the placebo-treated subjects were similar, Depakote ER-treatedpatients had lower number of adverse events compared to the DepakoteDR-treated patients. It can be deduced that the reduced adverse eventsseen with Depakote ER treatment compared to Depakote DR treatment isprobably due to the expected lower maximal plasma concentrations(C_(max)) and DFL that would be achieved, as illustrated in Examples 3 &4, following administration of equal doses of two the formulations. Itis reasonably believed that the reduced adverse effects, as well aslower frequency of dosing (once-a-day) dosing achieved with Depakote ER,would lead to better compliance.

[0189] The controlled release tablet formulations of the presentinvention thus provide an effective delivery system for the once dailyadministration of valproic acid (divalproex sodium) to patients in needof such treatment. The formulations of the invention providesubstantially level plasma concentrations of valproic acid fallingwithin the therapeutic range of the drug over a period which permitsadministration once daily. Further the incidence of side effectsassociated with valproate therapy has been reduced with this newformulation.

[0190] While there have been shown and described what are the preferredembodiments of the invention, one skilled in the pharmaceuticalformulation art will appreciate that various modifications in theformulations and process can be made without departing from the scope ofthe invention as it is defined by the appended claims.

We claim:
 1. A oral polymeric controlled release formulation suitablefor once-a-day administration comprising: a) divalproex sodium; b) saiddivalproex sodium is in association with a sufficient quantity of apharmaceutically acceptable polymer, and; c) when said formulation isingested orally, said formulation produces a C_(max) that isstatistically significantly lower than the C_(max) produced by a delayedrelease divalproex sodium tablet, when each is determined at steadystate in a fasting population.
 2. The formulation according to claim 1which produces a C_(min) that is not statistically significantlydifferent from the C_(min) produced by said delayed release divalproexsodium tablet, when each is determined at steady state in a fastingpopulation.
 3. The formulation according to claim 1 in which saidformulation produces an AUC value that is equivalent to the AUC valuegenerated by said divalproex sodium delayed release tablet, when each isdetermined at steady state in a fasting population.
 4. The formulationaccording to claim 1 which: a) produces a C_(min) that is notstatistically significantly different from the C_(min) produced by saiddelayed release divalproex sodium tablet, when each is determined atsteady state in a fasting population, and; b) said formulation producesan AUC value that is equivalent to the AUC value generated by saiddivalproex sodium delayed release tablet, when each is determined atsteady state in a fasting population.
 5. The formulation according toclaim 4 which produces a DFL that is lower than the DFL produced saiddelayed release divalproex sodium tablet, when each is determined atsteady state in a fasting population.
 6. The formulation according toclaim 1 in which said formulation is a matrix system, an osmotic pumpsystem or a reservoir polymeric system.
 7. A oral polymeric controlledrelease formulation suitable for once-a-day administration comprising:a) divalproex sodium; b) said divalproex sodium is in association with apharmaceutically acceptable polymer, and; c) when said formulation isingested orally said formulation produces: i. a C_(max) that isstatistically significantly lower than the C_(max) produced by a delayedrelease divalproex sodium tablet, when each C_(max) is determined atsteady state in a fasting population, ii. a C_(min) that is notstatistically significantly different from the C_(min) produced by saiddelayed release divalproex sodium tablet, when each C_(min) isdetermined at steady state in a fasting population, and; iii. saidformulation produces an AUC value that is equivalent to the AUC valuegenerated by said divalproex sodium delayed release tablet, when eachAUC is determined at steady state in a fasting population.
 8. Theformulation according to claim 7 in which said formulation producessteady state peak plasma valproate levels that are about 10 to about 20%lower than that produced by a said delayed release divalproex sodiumtablet.
 9. A method for the treatment of migraine comprising theadministration of a formulation according to claim 1 to a patient inneed thereof.
 10. A method for the treatment of epilepsy comprising theadministration of a formulation according to claim 1 to a patient inneed thereof.
 11. A method for the treatment of mania associated with abipolar disorder comprising the administration of a formulationaccording to claim 1 to a patient in need thereof.
 12. A method for thereduction of side effects associated with divalproex sodium therapycomprising the administration of a formulation according to claim 1 .13. A oral polymeric controlled release formulation suitable foronce-a-day administration comprising: a) a valproate compound; b) saidvalproate compound is in association with a sufficient quantity of apharmaceutically acceptable polymer, and; c) when said formulation isingested orally, said formulation produces a C_(max) that isstatistically significantly lower than the C_(max) produced by a biddosage form of said valproate compound, when each is determined atsteady state in a fasting population.
 14. The formulation according toclaim 13 which produces a C_(min) that is not statisticallysignificantly different from the C_(min) produced by said bid dosageform when each is determined at steady state in a fasting population.15. The formulation according to claim 13 in which said formulationproduces an AUC value that is equivalent to the AUC value generated bysaid bid valproate dosage form, when each is determined at steady statein a fasting population.
 16. The formulation according to claim 13which: a) produces a C_(min) that is not statistically significantlydifferent from the C_(min) produced by said bid valproate dosage form ,when each is determined at steady state in a fasting population, and; b)said formulation produces an AUC value that is equivalent to the AUCvalue generated by said bid valproate dosage form, when each isdetermined at steady state in a fasting population.
 17. The formulationaccording to claim 13 which produces a DFL that is not statisticallysignificantly different than the DFL by produced said bid valproatedosage form, when each is determined at steady state in a fastingpopulation.
 18. The formulation according to claim 13 in which saidformulation is a matrix system, an osmotic pump system or a reservoirpolymeric system.
 19. An oral matrix formulation suitable for once-a-dayadministration comprising: a) from about 40 to about 80 w/w % ofdivalproex sodium; b) a sufficient quantity of a pharmaceuticallyacceptable polymer, and; c) when said formulation is ingested orally: i.said formulation produces a C_(max) that is statistically significantlylower than the C_(max) produced by a delayed release divalproex sodiumtablet, when each is determined at steady state in a fasting population,ii. a C_(min) that is not statistically significantly different from theC_(min) produced by said delayed release divalproex sodium tablet, wheneach C_(min) is determined at steady state in a fasting population, and;iii. said formulation produces an AUC value that is equivalent to theAUC value generated by said divalproex sodium delayed release tablet,when each AUC is determined at steady state in a fasting population. 20.A oral osmotic pump formulation suitable for once-a-day administrationcomprising: a) divalproex sodium; b) said divalproex sodium is inassociation with a sufficient quantity of a pharmaceutically acceptablesemipermeable polymer, and; c) when said formulation is ingested orally:i. said formulation produces a C_(max) that is statisticallysignificantly lower than the C_(max) produced by a delayed releasedivalproex sodium tablet, when each is determined at steady state in afasting population, ii. a C_(min) that is not statisticallysignificantly different from the C_(min) produced by said delayedrelease divalproex sodium tablet, when each C_(min) is determined atsteady state in a fasting population, and; iii. said formulationproduces an AUC value that is equivalent to the AUC value generated bysaid divalproex sodium delayed release tablet, when each AUC isdetermined at steady state in a fasting population.
 21. A reservoirpolymeric formulation suitable for once-a-day administration comprising:a) divalproex sodium; b) said divalproex sodium is in association with asufficient quantity of a pharmaceutically acceptable polymer, and; c)when said formulation is ingested orally: i. said formulation produces aC_(max) that is statistically significantly lower than the C_(max)produced by a delayed release divalproex sodium tablet, when each isdetermined at steady state in a fasting population, ii. a C_(min) thatis not statistically significantly different from the C_(min) producedby said delayed release divalproex sodium tablet, when each C_(min) isdetermined at steady state in a fasting population, and; iii. saidformulation produces an AUC value that is equivalent to the AUC valuegenerated by said divalproex sodium delayed release tablet, when eachAUC is determined at steady state in a fasting population.